1T4E

Structure of Human MDM2 in complex with a Benzodiazepine Inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.239 

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This is version 1.5 of the entry. See complete history. 


Literature

Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells

Grasberger, B.L., Lu, T., Schubert, C., Parks, D.J., Carver, T.E., Koblish, H.K., Cummings, M.D., LaFrance, L.V.

(2005) J Med Chem 48: 909-912

  • DOI: https://doi.org/10.1021/jm049137g
  • Primary Citation of Related Structures:  
    1T4E, 1T4F

  • PubMed Abstract: 

    HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.

    • Organizational Affiliation: 

    Johnson & Johnson Pharmaceutical Research & Development L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA. bgrasber@prdus.jnj.com


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ubiquitin-protein ligase E3 Mdm2
A, B
96Homo sapiensMutation(s): 0 
Gene Names: MDM2
EC: 6.3.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q00987 (Homo sapiens)
Explore Q00987 
Go to UniProtKB:  Q00987
PHAROS:  Q00987
GTEx:  ENSG00000135679 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00987
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DIZ
Query on DIZ
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		(4-CHLOROPHENYL)[3-(4-CHLOROPHENYL)-7-IODO-2,5-DIOXO-1,2,3,5-TETRAHYDRO-4H-1,4-BENZODIAZEPIN-4-YL]ACETIC ACID
C23 H15 Cl2 I N2 O4
HQEQUYKKMMKSSX-PMACEKPBSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
DIZ BindingDB:  1T4E Kd: min: 67, max: 80 (nM) from 2 assay(s)
IC50: min: 200, max: 420 (nM) from 2 assay(s)
PDBBind:  1T4E Kd: 80 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.239 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.486α = 90
b = 98.486β = 90
c = 74.038γ = 120
Software Package:
Software NamePurpose
CNXrefinement
PROTEUM PLUSdata reduction
PROTEUM PLUSdata scaling
CNXphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-02-08
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2011-11-16
    Changes: Atomic model
  • Version 1.4: 2018-01-31
    Changes: Experimental preparation
  • Version 1.5: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description